Trafficking of monocytes and macrophages plays a critical role in atherosclerosis, resistance to intracellular pathogens, and antigen presentation, but the signals that regulate this trafficking are not well understood. The overall goal of this application is to elucidate the role of chemokine receptor 2 (CCR2), the receptor for the monocyte chemoattractant proteins (MCPs) in maintenance of atherosclerotic lesions, in resistance to intracellular pathogens, and in the development of type 1 (Thl) polarized immune responses. During the first two funding cycles of this grant we have cloned CCR2, and shown that CCR2 -/- mice develop less atherosclerosis than wild-type littermate controls. In the current application we will extend those findings, and will use newly created human CCR2 knock-in mice to test the hypothesis that CCR2 antagonists will regress atherosclerotic lesions. We will transplant segments of the aorta between wild-type and CCR2 -/- mice to provide a second, independent method for evaluating the role of CCR2 in lesion regression. Experiments in this application will utilize a novel system of conditional expression of reporter genes in transgenic mice to obtain kinetic information on macrophage efflux from simple to complex lesions. Work from our group and others has shown that CCR2-/- mice have a marked impairment in their ability to make interferon gamma, and this may contribute to their susceptibility to intracellular pathogens. We will use CCR2-/- and MCP-I -/- mice to elucidate the basis for this cytokine production defect. Recent results from our newly created MCP-5 -/- mice suggest a model in which MCP-1 attracts cells to the site of immunization/infection, and MCP-5 directs cells to the draining lymph node. We will extend those studies, and test the hypothesis that different members of the MCP-family of chemokines are preferentially expressed in different tissues. Completion of the specific aims of this grant will provide new data on the role of CCR2 in the maintenance and regression of atherosclerotic lesions, and in the trafficking of antigen presenting cells and the development of polarized T cell responses. This data will speak directly to the therapeutic prospects for CCR2 antagonists.